ABSTRACT- NEUROPATHOLOGY CORE The Neuropathology (NP) Core provides for diagnostic neuropathological evaluations of: 1) patients and control subjects enrolled in the Clinical Core (CC), and 2) other clinically well documented patients with neurodegenerative disease. The NP Core aims to enhance understanding of the heterogeneity of AD/ADRD to develop better biomarkers and discover novel and effective therapeutic approaches that promote progress towards achieving the NAPA research implementation milestones. The protocols used by the NP Core will be state of the art and consistent with 21st century brain banking procedures. These will be essential to meet the increasingly sophisticated needs of the AD research community. We will emphasize delineating the presence of overlapping neurodegenerative syndromes. In this renewal, we will continue to emphasize the central theme of the NYU ADRC: elucidating the clinico-pathological substrates that underlie the transitions between normal aging, subjective cognitive decline (SCD), MCI, and dementia to help develop novel interventions that delay or prevent these transitions. The overall objectives of the NP Core of the NYULH ADRC are to provide staff, technical resources, laboratory facilities, and expertise to investigate the structural and molecular properties of the brains of both patients with ADRC and those of normal controls. Aims 1?3 of the NP core encompass the key neuropathology functions of the NP Core. Aims 4 and 5 will develop innovative neuropathological technologies. The emerging clinical evaluation system of ATN?which is proposed to underlie transitional stages between normal aging to SCD, SCD to MCI, and MCI to early dementia?needs to be correlated with comprehensive neuropathological measures that also reflect disease heterogeneity. In addition, while brain tissue is an essential resource, it cannot be developed into dynamic cellular models. Hence, the NP Core has launched a new induced pluripotent stem cell (iPSC) program, providing investigators with an easily replenished source of tissue to address key questions about the heterogeneous pathogenesis of AD/ADRC. Aims 6 and 7 focus on using NP Core resources to train the next generation of neuropathologists and translational neuroscientists conducting research on AD/ADRD, support their studies to develop novel therapeutic targets, and promote educational outreach about brain and biospecimen donation. The combination of these aims will help the NP Core to develop better biomarkers and to discover novel effective, therapeutic approaches; hence, accelerating progress towards achieving the NAPA research implementation milestones.